nmpЖурнал им. Н.В. Склифосовского «Неотложная медицинская помощь»Russian Sklifosovsky Journal "Emergency Medical Care"2223-90222541-8017“N.V. Sklifosovsky Research Institute for Emergency Medicine”10.23934/2223-9022-2022-11-3-484-492nmp-1451Research ArticleОБЗОР ЛИТЕРАТУРЫREVIEWSИммунопатогенез острого панкреатитаImmunopathogenesis of Acute Pancreatitishttps://orcid.org/0000-0002-1244-2135БулаваГ. В.BulavaG. V.

Булава Галина Владимировна доктор медицинских наук, научный консультант, лаборатория клинической иммунологии

129090, Москва, Б. Сухаревская пл., д. 3

Galina V. Bulava Doctor of Medical Sciences, Scientific Consultant, Laboratory of Clinical Immunology

129090, Moscow, B. Sukharevskaya Sq., 3

gbulava@mail.ruГБУЗ «Научно-исследовательский институт скорой помощи им. Н.В. Склифосовского ДЗМ»РоссияN.V. Sklifosovsky Research Institute for Emergency MedicineRussian Federation202217102022113484492Copyright © Булава Г.В., 20222022Булава Г.В.Bulava G.V.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.jnmp.ru/jour/article/view/1451

Лидирующие позиции по частоте, тяжести течения и высокой смертности занимают инфицированные формы острого панкреатита. Однако изучены не все патофизиологические механизмы развития этой патологии. С учетом того, что иммунные реакции являются неотъемлемой частью патогенеза панкреатита, крайне важно изучить взаимосвязь механизмов воспаления и активации иммунного ответа. В этом обзоре будет обсуждена роль различных популяций клеток врожденного иммунитета, включая макрофаги, нейтрофилы, дендритные и тучные клетки, и регуляторных иммунных клеток в патогенезе деструкции тканей железы и взаимосвязи иммунных реакций и синдрома системного воспалительного ответа. Нацеливание на популяции врожденных иммунных клеток и сигнальные пути метаболитов при остром панкреатите может привести к более широкому и, в конечном счете, более эффективному изменению направления программы лечения в сторону разрешения заболевания и улучшения клинических результатов.

The leading positions in terms of frequency, severity of the course and high mortality belong to infectious forms of acute pancreatitis. However, not all pathophysiological mechanisms of the development of this disorder have been studied. Given that immune responses are an integral part of the pathogenesis of pancreatitis, it is extremely important to study the relationship between the mechanisms of inflammation and activation of the immune response. This review will discuss the role of various populations of innate immune cells, including macrophages, neutrophils, dendritic and mast cells, and regulatory immune cells in the pathogenesis of gland tissue destruction and the relationship between immune responses and systemic inflammatory response syndrome. Targeting innate immune cell populations and metabolite signaling pathways in acute pancreatitis may lead to a broader and ultimately more effective redirection of the treatment program towards disease resolution and improved clinical outcomes.

острый панкреатитсиндром системного воспалительного ответа (SIRS)клетки врожденного и адаптивного иммунитетацитокиныаcute pancreatitissystemic inflammatory response syndrome (SIRS)innate and adaptive immune cellscytokinesReferencesАбакумов М.М., Багненко С.Ф., Белобородов В.Б., Белоцерковский Б.З., Беляев А.М., Бурневич С.З., и др. Абдоминальная хирургическая инфекция. Москва; 2011.Abakumov MM, Bagnenko SF, Beloborodov VB, Belotserkovskiy BZ, Belyaev AM, Burnevich SZ, et al. Abdominal’naya khirurgicheskaya infektsiya. Moscow; 2011. (in Russ.)Watanabe T, Kudo M, Strober W. Immunopathogenesis of pancreatitis. Mucosal Immunol. 2017;10(2):283–298. PMID:27848953 https://doi.org/10.1038/mi.2016.101Watanabe T, Kudo M, Strober W. Immunopathogenesis of pancreatitis. Mucosal Immunol. 2017;10(2):283–298. PMID:27848953 https://doi.org/10.1038/mi.2016.101van Till JWO, van Veen SQ, van Ruler O, Lamme B, Gouma DJ, Boermeester MA. The innate immune response to secondary peritonitis. Shock. 2007;28(5):504–517. PMID:17589378 https://doi.org/10.1097/shk.0b013e318063e6cavan Till JWO, van Veen SQ, van Ruler O, Lamme B, Gouma DJ, Boermeester MA. The innate immune response to secondary peritonitis. Shock. 2007;28(5):504–517. PMID:17589378 https://doi.org/10.1097/shk.0b013e318063e6caLiu M, Silva-Sanchez A, Randall TD, Meza-Perez S. Specialized immune responses in the peritoneal cavity and omentum. J Leukoc Biol. 2021;109(4):717–729. PMID:32881077 https://doi.org/10.1002/JLB.5MIR0720-271RRLiu M, Silva-Sanchez A, Randall TD, Meza-Perez S. Specialized immune responses in the peritoneal cavity and omentum. J Leukoc Biol. 2021;109(4):717–729. PMID:32881077 https://doi.org/10.1002/JLB.5MIR0720-271RRGukovsky I, Li N, Todoric J, Gukovskaya A, Karin M. Inflammation, autophagy, and obesity: common features in the pathogenesis of pancreatitis and pancreatic cancer. Gastroenterology. 2013;144(6):1199–209. PMID:23622129 https://doi.org/10.1053/j.gastro.2013.02.007Gukovsky I, Li N, Todoric J, Gukovskaya A, Karin M. Inflammation, autophagy, and obesity: common features in the pathogenesis of pancreatitis and pancreatic cancer. Gastroenterology. 2013;144(6):1199–1209. PMID:23622129 https://doi.org/10.1053/j.gastro.2013.02.007Mayerle J, Sendler M, Hegyi E, Beyer G, Lerch MM, Sahin-Tóth M. Genetics, Cell Biology, and Pathophysiology of Pancreatitis. Gastroenterology. 2019;156(7):1951–1968. PMID:30660731 https://doi.org/10.1053/j.gastro.2018.11.081Mayerle J, Sendler M, Hegyi E, Beyer G, Lerch MM, Sahin-Tóth M. Genetics, Cell Biology, and Pathophysiology of Pancreatitis. Gastroenterology. 2019;156(7):1951–1968. PMID:30660731 https://doi.org/10.1053/j.gastro.2018.11.081Hoque R, Malik AF, Gorelick F, Mehal WZ. Sterile inflammatory response in acute pancreatitis. Pancreas. 2012;41(3):353–357. PMID:22415665 https://doi.org/10.1097/MPA.0b013e3182321500Hoque R, Malik AF, Gorelick F, Mehal WZ. Sterile inflammatory response in acute pancreatitis. Pancreas. 2012;41(3):353–357. PMID:22415665 https://doi.org/10.1097/MPA.0b013e3182321500Kang R, Zhang Q, Hou W, Yan Z, Chen R, Bonaroti J, et al. Intracellular Hmgb1 inhibits inflammatory nucleosome release and limits acute pancreatitis in mice. Gastroenterology. 2014;146(4):1097–1107. PMID:24361123 https://doi.org/10.1053/j.gastro.2013.12.015Kang R, Zhang Q, Hou W, Yan Z, Chen R, Bonaroti J, et al. Intracellular Hmgb1 inhibits inflammatory nucleosome release and limits acute pancreatitis in mice. Gastroenterology. 2014;146(4):1097–1107. PMID:24361123 https://doi.org/10.1053/j.gastro.2013.12.015Sarhan M, Land WG, Tonnus W, Hugo CP, Linkermann A. Origin and Consequences of Necroinflammation. Physiol Rev. 2018;98(2):727–780. PMID:29465288 https://doi.org/10.1152/physrev.00041.2016Sarhan M, Land WG, Tonnus W, Hugo CP, Linkermann A. Origin and Consequences of Necroinflammation. Physiol Rev. 2018;98(2):727–780. PMID:29465288 https://doi.org/10.1152/physrev.00041.2016Peng C, Li Z, Yu X. The Role of Pancreatic Infiltrating Innate Immune Cells in Acute Pancreatitis. Int J Med Sci. 2021;18(2):534–545. PMID:33390823 https://doi.org/10.7150/ijms.51618Peng C, Li Z, Yu X. The Role of Pancreatic Infiltrating Innate Immune Cells in Acute Pancreatitis. Int J Med Sci. 2021;18(2):534–545. PMID:33390823 https://doi.org/10.7150/ijms.51618Xue J, Sharma V, Habtezion A. Immune cells and immune-based therapy in pancreatitis. Immunol Res. 2014;58(2–3):378–386. PMID:24710635 https://doi.org/10.1007/s12026-014-8504-5Xue J, Sharma V, Habtezion A. Immune cells and immune-based therapy in pancreatitis. Immunol Res. 2014;58(2–3):378–386. PMID:24710635 https://doi.org/10.1007/s12026-014-8504-5Antonucci L, Fagman JB, Kim JY, Todoric J, Gukovsky I, Mackey M, et al. Basal autophagy maintains pancreatic acinar cell homeostasis and protein synthesis and prevents ER stress. Proc Natl Acad Sci USA. 2015;112(45):E6166–6174. PMID:26512112 https://doi.org/10.1073/pnas.1519384112Antonucci L, Fagman JB, Kim JY, Todoric J, Gukovsky I, Mackey M, et al. Basal autophagy maintains pancreatic acinar cell homeostasis and protein synthesis and prevents ER stress. Proc Natl Acad Sci USA. 2015;112(45):E6166–6174. PMID:26512112 https://doi.org/10.1073/pnas.1519384112Wan J, Yang X, Ren Y, Li X, Zhu Y, Haddock AN, et al. Inhibition of miR-155 reduces impaired autophagy and improves prognosis in an experimental pancreatitis mouse model. Cell Death Dis. 2019;10(4):303. PMID:30944299 https://doi.org/10.1038/s41419-019-1545-xWan J, Yang X, Ren Y, Li X, Zhu Y, Haddock AN, et al. Inhibition of miR-155 reduces impaired autophagy and improves prognosis in an experimental pancreatitis mouse model. Cell Death Dis. 2019;10(4):303. PMID:30944299 https://doi.org/10.1038/s41419-019-1545-xBedrosian AS, Nguyen AH, Hackman M, Connolly MK, Malhotra A, Ibrahim J, et al. Dendritic cells promote pancreatic viability in mice with acute pancreatitis. Gastroenterology. 2011;141(5):1915–1926. PMID:21801698 https://doi.org/10.1053/j.gastro.2011.07.033Bedrosian AS, Nguyen AH, Hackman M, Connolly MK, Malhotra A, Ibrahim J, et al. Dendritic cells promote pancreatic viability in mice with acute pancreatitis. Gastroenterology. 2011;141(5):1915–1926. PMID:21801698 https://doi.org/10.1053/j.gastro.2011.07.033Lopez-Font I, Gea-Sorlí S, de-Madaria E, Gutiérrez LM, PérezMateo M, Closa D. Pancreatic and pulmonary mast cells activation during experimental acute pancreatitis. World J Gastroenterol. 2010;16(27):3411–3417. PMID:20632444 https://doi.org/10.3748/wjg.v16.i27.3411Lopez-Font I, Gea-Sorlí S, de-Madaria E, Gutiérrez LM, PérezMateo M, Closa D. Pancreatic and pulmonary mast cells activation during experimental acute pancreatitis. World J Gastroenterol. 2010;16(27):3411–3417. PMID:20632444 https://doi.org/10.3748/wjg.v16.i27.3411Shifrin AL, Chirmule N, Gao GP, Wilson JM, Raper SE. Innate immune responses to adenoviral vector-mediated acute pancreatitis. Pancreas. 2005;30(2):122–129. PMID:15714134 https://doi.org/10.1097/01.mpa.0000151578.99413.88Shifrin AL, Chirmule N, Gao GP, Wilson JM, Raper SE. Innate immune responses to adenoviral vector-mediated acute pancreatitis. Pancreas. 2005;30(2):122–129. PMID:15714134 https://doi.org/10.1097/01.mpa.0000151578.99413.88Son A, Ahuja M, Schwartz DM, Varga A, Swaim W, Kang N, et al. Ca(2+) Influx Channel Inhibitor SARAF Protects Mice From Acute Pancreatitis. Gastroenterology. 2019;157(6):1660–1672. PMID:31493399 https://doi.org/10.1053/j.gastro.2019.08.042Son A, Ahuja M, Schwartz DM, Varga A, Swaim W, Kang N, et al. Ca(2+) Influx Channel Inhibitor SARAF Protects Mice From Acute Pancreatitis. Gastroenterology. 2019;157(6):1660–1672. PMID:31493399 https://doi.org/10.1053/j.gastro.2019.08.042Sendler M, Dummer A, Weiss FU, Krüger B, Wartmann T, ScharffetterKochanek K, et al. Tumour necrosis factor α secretion induces protease activation and acinar cell necrosis in acute experimental pancreatitis in mice. Gut. 2013;62(3):430–439. PMID:22490516 https://doi.org/10.1136/gutjnl-2011-300771Sendler M, Dummer A, Weiss FU, Krüger B, Wartmann T, ScharffetterKochanek K, et al. Tumour necrosis factor α secretion induces protease activation and acinar cell necrosis in acute experimental pancreatitis in mice. Gut. 2013;62(3):430–439. PMID:22490516 https://doi.org/10.1136/gutjnl-2011-300771Sendler M, Weiss FU, Golchert J, Homuth G, van den Brandt C, Mahajan UM, et al. Cathepsin B-Mediated Activation of Trypsinogen in Endocytosing Macrophages Increases Severity of Pancreatitis in Mice. Gastroenterology. 2018;154(3):704–718. PMID: 29079517 https://doi.org/10.1053/j.gastro.2017.10.018Sendler M, Weiss FU, Golchert J, Homuth G, van den Brandt C, Mahajan UM, et al. Cathepsin B-Mediated Activation of Trypsinogen in Endocytosing Macrophages Increases Severity of Pancreatitis in Mice. Gastroenterology. 2018;154(3):704–718. PMID:29079517 https://doi.org/10.1053/j.gastro.2017.10.018van Dijk SM, Hallensleben NDL, van Santvoort HC, Fockens P, van Goor H, Bruno MJ, et al. Acute pancreatitis: recent advances through randomised trials. Gut. 2017;66(11):2024–2032. PMID:28838972 https://doi.org/10.1136/gutjnl-2016-313595van Dijk SM, Hallensleben NDL, van Santvoort HC, Fockens P, van Goor H, Bruno MJ, et al. Acute pancreatitis: recent advances through randomised trials. Gut. 2017;66(11):2024–2032. PMID:28838972 https://doi.org/10.1136/gutjnl-2016-313595Banks PA, Bollen TL, Dervenis C, Gooszen HG, Johnson CD, Sarr MG, et al. Classification of acute pancreatitis--2012: revision of the Atlanta classification and definitions by international consensus. Gut. 2013;62(1):102–111. PMID:23100216 https://doi.org/10.1136/gutjnl2012-302779Banks PA, Bollen TL, Dervenis C, Gooszen HG, Johnson CD, Sarr MG, et al. Classification of acute pancreatitis--2012: revision of the Atlanta classification and definitions by international consensus. Gut. 2013;62(1):102–111. PMID:23100216 https://doi.org/10.1136/gutjnl2012-302779Tan C, Yang L, Shi F, Hu J, Zhang X, Wang Y, et al. Early Systemic Inflammatory Response Syndrome Duration Predicts Infected Pancreatic Necrosis. J Gastrointest Surg. 2020;24(3):590–597. PMID:30891659 https://doi.org/10.1007/s11605-019-04149-5Tan C, Yang L, Shi F, Hu J, Zhang X, Wang Y, et al. Early Systemic Inflammatory Response Syndrome Duration Predicts Infected Pancreatic Necrosis. J Gastrointest Surg. 2020;24(3):590–597. PMID:30891659 https://doi.org/10.1007/s11605-019-04149-5Castanheira FVS, Kubes P. Neutrophils and NETs in modulating acute and chronic inflammation. Blood. 2019;133(20):2178–2Castanheira FVS, Kubes P. Neutrophils and NETs in modulating acute and chronic inflammation. Blood. 2019;133(20):2178–2185. PMID:30898862 https://doi.org/10.1182/blood-2018-11-844530Sônego F, Castanheira FV, Ferreira RG, Kanashiro A, Leite CA, Nascimento DC, et al. Paradoxical Roles of the Neutrophil in Sepsis: Protective and Deleterious. Front Immunol. 2016;7:155. PMID:27199981 https://doi.org/10.3389/fimmu.2016.00155Sônego F, Castanheira FV, Ferreira RG, Kanashiro A, Leite CA, Nascimento DC, et al. Paradoxical Roles of the Neutrophil in Sepsis: Protective and Deleterious. Front Immunol. 2016;7:155. PMID:27199981 https://doi.org/10.3389/fimmu.2016.00155Jorch SK and Kubes P. An emerging role for neutrophil extracellular traps in noninfectious disease. Nat Med. 2017;23(3):279–287. PMID:28267716 https://doi.org/10.1038/nm.4294Jorch SK and Kubes P. An emerging role for neutrophil extracellular traps in noninfectious disease. Nat Med. 2017;23(3):279–287. PMID:28267716 https://doi.org/10.1038/nm.4294Huang H, Tohme S, Al-Khafaji AB, Tai S, Loughran P, Chen L, et al. Damage-associated molecular pattern-activated neutrophil extracellular trap exacerbates sterile inflammatory liver injury. Hepatology. 2015;62(2):600–614. PMID:25855125 https://doi.org/10.1002/hep.27841Huang H, Tohme S, Al-Khafaji AB, Tai S, Loughran P, Chen L, et al. Damage-associated molecular pattern-activated neutrophil extracellular trap exacerbates sterile inflammatory liver injury. Hepatology. 2015;62(2):600–614. PMID:25855125 https://doi.org/10.1002/hep.27841Brinkmann V, Reichard U, Goosmann C, Fauler B, Uhlemann Y, Weiss DS, et al. Neutrophil extracellular traps kill bacteria. Science. 2004;303(5663):1532–1535. PMID:15001782 https://doi.org/10.1126/science.1092385Brinkmann V, Reichard U, Goosmann C, Fauler B, Uhlemann Y, Weiss DS, et al. Neutrophil extracellular traps kill bacteria. Science. 2004;303(5663):1532–1535. PMID:15001782 https://doi.org/10.1126/science.1092385Zha C, Meng X, Li L, Mi S, Qian D, Li Z, et al. Neutrophil extracellular traps mediate the crosstalk between glioma progression and the tumor microenvironment via the HMGB1/RAGE/IL-8 axis. Cancer Biol Med. 2020;17(1):154–168. PMID:32296583 https://doi.org/10.20892/j.issn.2095-3941.2019.0353Zha C, Meng X, Li L, Mi S, Qian D, Li Z, et al. Neutrophil extracellular traps mediate the crosstalk between glioma progression and the tumor microenvironment via the HMGB1/RAGE/IL-8 axis. Cancer Biol Med. 2020;17(1):154–168. PMID:32296583 https://doi.org/10.20892/j.issn.2095-3941.2019.0353Rada B. Neutrophil Extracellular Traps. Methods Mol Biol. 2019;1982:517–528. PMID:31172493 https://doi.org/10.1007/978-1-4939-9424-3_31Rada B. Neutrophil Extracellular Traps. Methods Mol Biol. 2019;1982:517–528. PMID:31172493 https://doi.org/10.1007/978-1-4939-9424-3_31Воробьева Н.В., Пинегин Б.В. Внеклеточные ловушки нейтрофильных клеток: механизмы формирования и роль в здоровье и болезнях. Биохимия. 2014;79(12):1580–1591.Vorobjeva NV, Pinegin BV. Neutrophil Extracellular Traps: Mechanisms of Formation and Role in Health and Disease. Biochemistry (Moscow). 2014; 79(12):1286–1296.Steinberg BE, Grinstein S. Unconventional roles of the NADPH oxidase: signaling, ion homeostasis, and cell death. Sci STKE. 2007;2007(379): pe11. PMID:17392241 https://doi.org/10.1126/stke.3792007pe11Steinberg BE, Grinstein S. Unconventional roles of the NADPH oxidase: signaling, ion homeostasis, and cell death. Sci STKE. 2007;2007(379):pe11. PMID:17392241 https://doi.org/10.1126/stke.3792007pe11Beiter K, Wartha F, Albiger B, Normark S, Zychlinsky A, HenriquesNormark B. An endonuclease allows Streptococcus pneumoniae to escape from neutrophil extracellular traps. Curr Biol. 2006;16(4):401–407. PMID:16488875 https://doi.org/10.1016/j.cub.2006.01.056Beiter K, Wartha F, Albiger B, Normark S, Zychlinsky A, HenriquesNormark B. An endonuclease allows Streptococcus pneumoniae to escape from neutrophil extracellular traps. Curr Biol. 2006;16(4):401–407. PMID:16488875 https://doi.org/10.1016/j.cub.2006.01.056Berends ET, Horswill AR, Haste NM, Monestier M, Nizet V, von Köckritz-Blickwede M. Nuclease expression by Staphylococcus aureus facilitates escape from neutrophil extracellular traps. J Innate Immun. 2010;2(6):576–586. PMID:20829609 https://doi.org/10.1159/000319909Berends ET, Horswill AR, Haste NM, Monestier M, Nizet V, von Köckritz-Blickwede M. Nuclease expression by Staphylococcus aureus facilitates escape from neutrophil extracellular traps. J Innate Immun. 2010;2(6):576–586. PMID:20829609 https://doi.org/10.1159/000319909Thammavongsa V, Missiakas DM, Schneewind O. Staphylococcus aureus degrades neutrophil extracellular traps to promote immune cell death. Science. 2013;342(6160):863–866. PMID:24233725 https://doi.org/10.1126/science.1242255Thammavongsa V, Missiakas DM, Schneewind O. Staphylococcus aureus degrades neutrophil extracellular traps to promote immune cell death. Science. 2013;342(6160):863–866. PMID:24233725 https://doi.org/10.1126/science.1242255Rosales C. Neutrophils at the crossroads of innate and adaptive immunity. J Leukoc Biol. 2020;108(1):377–396. PMID:32202340 https://doi.org/10.1002/JLB.4MIR0220-574RRRosales C. Neutrophils at the crossroads of innate and adaptive immunity. J Leukoc Biol. 2020;108(1):377–396. PMID:32202340 https://doi.org/10.1002/JLB.4MIR0220-574RRHines OJ, Pandol SJ. Management of severe acute pancreatitis. BMJ. 2019;367:l6227. PMID:31791953 https://doi.org/10.1136/bmj.l6227Hines OJ, Pandol SJ. Management of severe acute pancreatitis. BMJ. 2019;367:l6227. PMID:31791953 https://doi.org/10.1136/bmj.l6227Gukovskaya AS, Gukovsky I, Algül H, Habtezion A. Autophagy, Inflammation, and Immune Dysfunction in the Pathogenesis of Pancreatitis. Gastroenterology. 2017;153(5):1212–1226. PMID:28918190 https://doi.org/10.1053/j.gastro.2017.08.071Gukovskaya AS, Gukovsky I, Algül H, Habtezion A. Autophagy, Inflammation, and Immune Dysfunction in the Pathogenesis of Pancreatitis. Gastroenterology. 2017;153(5):1212–1226. PMID:28918190 https://doi.org/10.1053/j.gastro.2017.08.071Kovtun A, Messerer DAC, Scharffetter-Kochanek K, Huber-Lang M, Ignatius A. Neutrophils in Tissue Trauma of the Skin, Bone, and Lung: Two Sides of the Same Coin. J Immunol Res. 2018;2018:8173983. PMID:29850639 https://doi.org/10.1155/2018/8173983Kovtun A, Messerer DAC, Scharffetter-Kochanek K, Huber-Lang M, Ignatius A. Neutrophils in Tissue Trauma of the Skin, Bone, and Lung: Two Sides of the Same Coin. J Immunol Res. 2018;2018:8173983. PMID:29850639 https://doi.org/10.1155/2018/8173983Han X, Ni J, Wu Z, Wu J, Li B, Ye X, et al. Myeloid-specific dopamine D2 receptor signalling controls inflammation in acute pancreatitis via inhibiting M1 macrophage. Br J Pharmacol. 2020;177(13):2991–3008. PMID:32060901 https://doi.org/10.1111/bph.15026Han X, Ni J, Wu Z, Wu J, Li B, Ye X, et al. Myeloid-specific dopamine D2 receptor signalling controls inflammation in acute pancreatitis via inhibiting M1 macrophage. Br J Pharmacol. 2020;177(13):2991–3008. PMID:32060901 https://doi.org/10.1111/bph.15026Zhao Q, Wei Y, Pandol SJ, Li L, Habtezion A. STING Signaling Promotes Inflammation in Experimental Acute Pancreatitis. Gastroenterology. 2018;154(6):1822–1835. PMID:29425920 https://doi.org/10.1053/j.gastro.2018.01.065Zhao Q, Wei Y, Pandol SJ, Li L, Habtezion A. STING Signaling Promotes Inflammation in Experimental Acute Pancreatitis. Gastroenterology. 2018;154(6):1822–1835. PMID:29425920 https://doi.org/10.1053/j.gastro.2018.01.065Makhija R, Kingsnorth AN. Cytokine storm in acute pancreatitis. J Hepatobiliary Pancreat Surg. 2002;9(4):401–410. PMID:12483260 https://doi.org/10.1007/s005340200049Makhija R, Kingsnorth AN. Cytokine storm in acute pancreatitis. J Hepatobiliary Pancreat Surg. 2002;9(4):401–410. PMID:12483260 https://doi.org/10.1007/s005340200049Roch AM, Maatman TK, Cook TG, Wu HH, Merfeld-Clauss S, Traktuev DO, et al. Therapeutic Use of Adipose-Derived Stromal Cells in a Murine Model of Acute Pancreatitis. J Gastrointest Surg. 2020;24(1):67–75. PMID:31745900 https://doi.org/10.1007/s11605-019-04411-wRoch AM, Maatman TK, Cook TG, Wu HH, Merfeld-Clauss S, Traktuev DO, et al. Therapeutic Use of Adipose-Derived Stromal Cells in a Murine Model of Acute Pancreatitis. J Gastrointest Surg. 2020;24(1):67–75. PMID:31745900 https://doi.org/10.1007/s11605-019-04411-wFrank D, Vince JE. Pyroptosis versus necroptosis: similarities, differences, and crosstalk. Cell Death Differ. 2019;26(1):99–114. PMID:30341423 https://doi.org/10.1038/s41418-018-0212-6Frank D, Vince JE. Pyroptosis versus necroptosis: similarities, differences, and crosstalk. Cell Death Differ. 2019;26(1):99–114. PMID:30341423 https://doi.org/10.1038/s41418-018-0212-6Shi J, Gao W, Shao F. Pyroptosis: Gasdermin-Mediated Programmed Necrotic Cell Death. Trends Biochem Sci. 2017;42(4):245–254. PMID:27932073 https://doi.org/10.1016/j.tibs.2016.10.004Shi J, Gao W, Shao F. Pyroptosis: Gasdermin-Mediated Programmed Necrotic Cell Death. Trends Biochem Sci. 2017;42(4):245–254. PMID:27932073 https://doi.org/10.1016/j.tibs.2016.10.004Gordon S, Martinez-Pomares L. Physiological roles of macrophages. Pflugers Arch. 2017;469(3–4):365–374. PMID:28185068 https://doi.org/10.1007/s00424-017-1945-7Gordon S, Martinez-Pomares L. Physiological roles of macrophages. Pflugers Arch. 2017;469(3–4):365–374. PMID:28185068 https://doi.org/10.1007/s00424-017-1945-7Arango Duque G and Descoteaux A. Macrophage cytokines: involvement in immunity and infectious diseases. Front Immunol. 2014;5:491. PMID:25339958 https://doi.org/10.3389/fimmu.2014.00491Arango Duque G and Descoteaux A. Macrophage cytokines: involvement in immunity and infectious diseases. Front Immunol. 2014;5:491. PMID:25339958 https://doi.org/10.3389/fimmu.2014.00491Shapouri-Moghaddam A, Mohammadian S, Vazini H, Taghadosi M, Esmaeili SA, Mardani F, et al. Macrophage plasticity, polarization, and function in health and disease. J Cell Physiol. 2018;233(9):6425–6440. PMID:29319160 https://doi.org/10.1002/jcp.26429Shapouri-Moghaddam A, Mohammadian S, Vazini H, Taghadosi M, Esmaeili SA, Mardani F, et al. Macrophage plasticity, polarization, and function in health and disease. J Cell Physiol. 2018;233(9):6425–6440. PMID: 29319160 https://doi.org/10.1002/jcp.26429Murray PJ. Macrophage Polarization. Annu Rev Physiol. 2017;79:541–566. PMID:27813830 https://doi.org/10.1146/annurev-physiol-022516-034339Murray PJ. Macrophage Polarization. Annu Rev Physiol. 2017;79:541–566. PMID:27813830 https://doi.org/10.1146/annurev-physiol-022516-034339Su Z, Zhang P, Yu Y, Lu H, Liu Y, Ni P, et al. HMGB1 Facilitated Macrophage Reprogramming towards a Proinflammatory M1-like Phenotype in Experimental Autoimmune Myocarditis Development. Sci Rep. 2016;6:21884. PMID:26899795 https://doi.org/10.1038/srep21884Su Z, Zhang P, Yu Y, Lu H, Liu Y, Ni P, et al. HMGB1 Facilitated Macrophage Reprogramming towards a Proinflammatory M1-like Phenotype in Experimental Autoimmune Myocarditis Development. Sci Rep. 2016;6:21884. PMID:26899795 https://doi.org/10.1038/srep21884Yang J, Zhao Y, Zhang L, Fan H, Qi C, Zhang K, et al. RIPK3/MLKLMediated Neuronal Necroptosis Modulates the M1/M2 Polarization of Microglia/Macrophages in the Ischemic Cortex. Cereb Cortex. 2018;28(7):2622–2635. PMID:29746630 https://doi.org/10.1093/cercor/bhy089Yang J, Zhao Y, Zhang L, Fan H, Qi C, Zhang K, et al. RIPK3/MLKLMediated Neuronal Necroptosis Modulates the M1/M2 Polarization of Microglia/Macrophages in the Ischemic Cortex. Cereb Cortex. 2018;28(7):2622–2635. PMID:29746630 https://doi.org/10.1093/cercor/bhy089Wang J, Li R, Peng Z, Zhou W, Hu B, Rao X, et al. GTS-21 Reduces Inflammation in Acute Lung Injury by Regulating M1 Polarization and Function of Alveolar Macrophages. Shock. 2019;51(3):389–400. PMID:29608552 https://doi.org/10.1097/SHK.0000000000001144Wang J, Li R, Peng Z, Zhou W, Hu B, Rao X, et al. GTS-21 Reduces Inflammation in Acute Lung Injury by Regulating M1 Polarization and Function of Alveolar Macrophages. Shock. 2019;51(3):389–400. PMID:29608552 https://doi.org/10.1097/SHK.0000000000001144Han X, Ni J, Wu Z, Wu J, Li B, Ye X, et al. Myeloid-specific dopamine D2 receptor signalling controls inflammation in acute pancreatitis via inhibiting M1 macrophage. Br J Pharmacol. 2020;177(13):2991–3008. PMID:32060901 https://doi.org/10.1111/bph.15026Han X, Ni J, Wu Z, Wu J, Li B, Ye X, et al. Myeloid-specific dopamine D2 receptor signalling controls inflammation in acute pancreatitis via inhibiting M1 macrophage. Br J Pharmacol. 2020;177(13):2991–3008. PMID:32060901 https://doi.org/10.1111/bph.15026Wen S, Li X, Ling Y, Chen S, Deng Q, Yang L, et al. HMGB1- associated necroptosis and Kupffer cells M1 polarization underlies remote liver injury induced by intestinal ischemia/reperfusion in rats. Faseb J. 2020;34: 4384–4402. PMID:31961020 https://doi.org/10.1096/fj.201900817RWen S, Li X, Ling Y, Chen S, Deng Q, Yang L, et al. HMGB1- associated necroptosis and Kupffer cells M1 polarization underlies remote liver injury induced by intestinal ischemia/reperfusion in rats. Faseb J. 2020;34: 4384–4402. PMID:31961020 https://doi.org/10.1096/fj.201900817RLiu RH, Wen Y, Sun HY, Liu CY, Zhang YF, Yang Y, et al. Abdominal paracentesis drainage ameliorates severe acute pancreatitis in rats by regulating the polarization of peritoneal macrophages. World J Gastroenterol. 2018;24(1):5131–5143. PMID:30568390 https://doi.org/10.3748/wjg.v24.i45.5131Liu RH, Wen Y, Sun HY, Liu CY, Zhang YF, Yang Y, et al. Abdominal paracentesis drainage ameliorates severe acute pancreatitis in rats by regulating the polarization of peritoneal macrophages. World J Gastroenterol. 2018;24(1):5131–5143. PMID:30568390 https://doi.org/10.3748/wjg.v24.i45.5131Wu XB, Sun HY, Luo ZL, Cheng L, Duan XM, Ren JD. Plasma-derived exosomes contribute to pancreatitis-associated lung injury by triggering NLRP3-dependent pyroptosis in alveolar macrophages. Biochim Biophys Acta Mol Basis Dis. 2020;1866(5):165685. PMID:31953217 https://doi.org/10.1016/j.bbadis.2020.165685Wu XB, Sun HY, Luo ZL, Cheng L, Duan XM, Ren JD. Plasma-derived exosomes contribute to pancreatitis-associated lung injury by triggering NLRP3-dependent pyroptosis in alveolar macrophages. Biochim Biophys Acta Mol Basis Dis. 2020;1866(5):165685. PMID:31953217 https://doi.org/10.1016/j.bbadis.2020.165685Puhr S, Lee J, Zvezdova E, Zhou YJ and Liu K. Dendritic cell developmentHistory, advances, and open questions. Semin Immunol. 2015;27(6):388–396. PMID:27040276 https://doi.org/10.1016/j.smim.2016.03.012Puhr S, Lee J, Zvezdova E, Zhou YJ and Liu K. Dendritic cell developmentHistory, advances, and open questions. Semin Immunol. 2015;27(6):388–396. PMID:27040276 https://doi.org/10.1016/j.smim.2016.03.012Françozo MCS, Costa FRC, Guerra-Gomes IC, Silva JS and SestiCosta R. Dendritic cells and regulatory T cells expressing CCR4 provide resistance to coxsackievirus B5-induced pancreatitis. Sci Rep. 2019;9(1):14766. PMID:31611578 https://doi.org/10.1038/s41598-019-51311-9Françozo MCS, Costa FRC, Guerra-Gomes IC, Silva JS and SestiCosta R. Dendritic cells and regulatory T cells expressing CCR4 provide resistance to coxsackievirus B5-induced pancreatitis. Sci Rep. 2019;9(1):14766. PMID:31611578 https://doi.org/10.1038/s41598-019-51311-9Del Fresno C, Saz-Leal P, Enamorado M, Wculek SK, Martínez-Cano S, Blanco-Menéndez N, et al. DNGR-1 in dendritic cells limits tissue damage by dampening neutrophil recruitment. Science. 2018;362(6412):351–356. PMID:30337411 https://doi.org/10.1126/science.aan8423Del Fresno C, Saz-Leal P, Enamorado M, Wculek SK, Martínez-Cano S, Blanco-Menéndez N, et al. DNGR-1 in dendritic cells limits tissue damage by dampening neutrophil recruitment. Science. 2018;362(6412):351–356. PMID:30337411 https://doi.org/10.1126/science.aan8423Xu D, Xie R, Xu Z, Zhao Z, Ding M, Chen W, et al. mTOR-Myc axis drives acinar-to-dendritic cell transition and the CD4(+) T cell immune response in acute pancreatitis. Cell Death Dis. 2020;11(6):416. PMID:32488108 https://doi.org/10.1038/s41419-020-2517-xXu D, Xie R, Xu Z, Zhao Z, Ding M, Chen W, et al. mTOR-Myc axis drives acinar-to-dendritic cell transition and the CD4(+) T cell immune response in acute pancreatitis. Cell Death Dis. 2020;11(6):416. PMID:32488108 https://doi.org/10.1038/s41419-020-2517-xOchi A, Nguyen AH, Bedrosian AS, Mushlin HM, Zarbakhsh S, Barilla R, et al. MyD88 inhibition amplifies dendritic cell capacity to promote pancreatic carcinogenesis via Th2 cells. J Exp Med. 2012;209(9):1671–1687. PMID:22908323 https://doi.org/10.1084/jem.20111706Ochi A, Nguyen AH, Bedrosian AS, Mushlin HM, Zarbakhsh S, Barilla R, et al. MyD88 inhibition amplifies dendritic cell capacity to promote pancreatic carcinogenesis via Th2 cells. J Exp Med. 2012;209(9):1671–1687. PMID:22908323 https://doi.org/10.1084/jem.20111706Pan LL, Niu W, Fang X, Liang W, Li H, Chen W, et al. Clostridium butyricum Strains Suppress Experimental Acute Pancreatitis by Maintaining Intestinal Homeostasis. Mol Nutr Food Res. 2019;e1801419. PMID:31034143 https://doi.org/10.1002/mnfr.201801419Pan LL, Niu W, Fang X, Liang W, Li H, Chen W, et al. Clostridium butyricum Strains Suppress Experimental Acute Pancreatitis by Maintaining Intestinal Homeostasis. Mol Nutr Food Res. 2019;e1801419. PMID:31034143 https://doi.org/10.1002/mnfr.201801419González-de-Olano D, Álvarez-Twose I. Mast Cells as Key Players in Allergy and Inflammation. J Investig Allergol Clin Immunol. 2018;28(6):365–378. PMID:30530385 https://doi.org/10.18176/jiaci.0327González-de-Olano D, Álvarez-Twose I. Mast Cells as Key Players in Allergy and Inflammation. J Investig Allergol Clin Immunol. 2018;28(6):365–378. PMID:30530385 https://doi.org/10.18176/jiaci.0327Yönetçi N, Oruç N, Ozütemiz AO, Celik HA, Yüce G. Effects of mast-cell stabilization in cerulein-induced acute pancreatitis in rats. Int J Pancreatol. 2001;29(3):163–171. PMID:12067220 https://doi.org/10.1385/IJGC:29:3:163Yönetçi N, Oruç N, Ozütemiz AO, Celik HA, Yüce G. Effects of mast-cell stabilization in cerulein-induced acute pancreatitis in rats. Int J Pancreatol. 2001;29(3):163–171. PMID:12067220 https://doi.org/10.1385/IJGC:29:3:163Dib M, Zhao X, Wang XD, Andersson R. Role of mast cells in the development of pancreatitis-induced multiple organ dysfunction. Br J Surg. 2002;89(2):172–178. PMID:11856129 https://doi.org/10.1046/j.0007-1323.2001.01991.xDib M, Zhao X, Wang XD, Andersson R. Role of mast cells in the development of pancreatitis-induced multiple organ dysfunction. Br J Surg. 2002;89(2):172–178. PMID:11856129 https://doi.org/10.1046/j.0007-1323.2001.01991.xKempuraj D, Twait EC, Williard DE, Yuan Z, Meyerholz DK, Samuel I. The novel cytokine interleukin-33 activates acinar cell proinflammatory pathways and induces acute pancreatic inflammation in mice. PLoS One. 2013;8(2):e56866. PMID:23418608 https://doi.org/10.1371/journal.pone.0056866Kempuraj D, Twait EC, Williard DE, Yuan Z, Meyerholz DK, Samuel I. The novel cytokine interleukin-33 activates acinar cell proinflammatory pathways and induces acute pancreatic inflammation in mice. PLoS One. 2013;8(2):e56866. PMID:23418608 https://doi.org/10.1371/journal.pone.0056866Leema G, Tamizhselvi R. Protective Effect of Scopoletin Against Cerulein-Induced Acute Pancreatitis and Associated Lung Injury in Mice. Pancreas. 2018;47:577–585. PMID:29595543 https://doi.org/10.1097/MPA.0000000000001034Leema G, Tamizhselvi R. Protective Effect of Scopoletin Against Cerulein-Induced Acute Pancreatitis and Associated Lung Injury in Mice. Pancreas. 2018;47:577–585. PMID:29595543 https://doi.org/10.1097/MPA.0000000000001034Zitti B and Bryceson YT. Natural killer cells in inflammation and autoimmunity. Cytokine Growth Factor Rev. 2018;42:37–46. PMID:30122459 https://doi.org/10.1016/j.cytogfr.2018.08.001Zitti B and Bryceson YT. Natural killer cells in inflammation and autoimmunity. Cytokine Growth Factor Rev. 2018;42:37–46. PMID:30122459 https://doi.org/10.1016/j.cytogfr.2018.08.001Mylona V, Koussoulas V, Tzivras D, Makrygiannis E, Georgopoulou P, Koratzanis G, et al. Changes in adaptive and innate immunity in patients with acute pancreatitis and systemic inflammatory response syndrome. Pancreatology. 2011; 11(5):475–481. PMID:21997439 https://doi.org/10.1159/000329460Mylona V, Koussoulas V, Tzivras D, Makrygiannis E, Georgopoulou P, Koratzanis G, et al. Changes in adaptive and innate immunity in patients with acute pancreatitis and systemic inflammatory response syndrome. Pancreatology. 2011; 11(5):475–481. PMID:21997439 https://doi.org/10.1159/000329460Wei X, Yao W, Li H, Qian J, Xie Y, Zhang Z, et al. B and NK Cells Closely Correlate with the Condition of Patients with Acute Pancreatitis. Gastroenterol Res Pract. 2019;2019:7568410. PMID:30881449 https://doi.org/10.1155/2019/7568410Wei X, Yao W, Li H, Qian J, Xie Y, Zhang Z, et al. B and NK Cells Closely Correlate with the Condition of Patients with Acute Pancreatitis. Gastroenterol Res Pract. 2019;2019:7568410. PMID:30881449 https://doi.org/10.1155/2019/7568410Ueda T, Takeyama Y, Yasuda T, Shinzeki M, Sawa H, Nakajima T, et al. Immunosuppression in patients with severe acute pancreatitis. J Gastroenterol. 2006;41(8):779–784. PMID:16988767 https://doi.org/10.1007/s00535-006-1852-8Ueda T, Takeyama Y, Yasuda T, Shinzeki M, Sawa H, Nakajima T, et al. Immunosuppression in patients with severe acute pancreatitis. J Gastroenterol. 2006;41(8):779–784. PMID:16988767 https://doi.org/10.1007/s00535-006-1852-8Dabrowski A, Osada J, Dabrowska MI, Wereszczynska-Siemiatkowska U. Monocyte subsets and natural killer cells in acute pancreatitis. Pancreatology. 2008;8(2):126–134. PMID:18382098 https://doi.org/10.1159/000123605Dabrowski A, Osada J, Dabrowska MI, Wereszczynska-Siemiatkowska U. Monocyte subsets and natural killer cells in acute pancreatitis. Pancreatology. 2008;8(2):126–134. PMID:18382098 https://doi.org/10.1159/000123605Yaseen MM, Abuharfeil NM, Darmani H, Daoud A. Yaseen MM, et al. Mechanisms of immune suppression by myeloid-derived suppressor cells: the role of interleukin-10 as a key immunoregulatory cytokine. Open Biol. 2020;10(9):200111. PMID:32931721 https://doi.org/10.1098/rsob.200111Yaseen MM, Abuharfeil NM, Darmani H, Daoud A. Mechanisms of immune suppression by myeloid-derived suppressor cells: the role of interleukin-10 as a key immunoregulatory cytokine. Open Biol. 2020;10(9):200111. PMID:32931721 https://doi.org/10.1098/rsob.200111Goldmann O, Beineke A, Medina E. Identification of a novel subset of myeloid-derived suppressor cells during chronic staphylococcal infection that resembles immature eosinophils. J Infect Dis. 2017;216(11):1444–1451. PMID:29029332 https://doi.org/10.1093/infdis/jix494Goldmann O, Beineke A, Medina E. Identification of a novel subset of myeloid-derived suppressor cells during chronic staphylococcal infection that resembles immature eosinophils. J Infect Dis. 2017;216(11):1444–1451. PMID:29029332 https://doi.org/10.1093/infdis/jix494Heim CE, Vidlak D, Kielian T. Interleukin-10 production by myeloidderived suppressor cells contributes to bacterial persistence during Staphylococcus aureus orthopedic biofilm infection. J Leukoc Biol. 2015;98(6):1003–1013. PMID:26232453 https://doi.org/10.1189/jlb.4VMA0315-125RRHeim CE, Vidlak D, Kielian T. Interleukin-10 production by myeloidderived suppressor cells contributes to bacterial persistence during Staphylococcus aureus orthopedic biofilm infection. J Leukoc Biol. 2015;98(6):1003–1013. PMID:26232453 https://doi.org/10.1189/jlb.4VMA0315-125RRBuckley CD, Gilroy DW, Serhan CN. Proresolving lipid mediators and mechanisms in the resolution of acute inflammation. Immunity. 2014;40(3):315–327. PMID:24656045 https://doi.org/10.1016/j.immuni.2014.02.009Buckley CD, Gilroy DW, Serhan CN. Proresolving lipid mediators and mechanisms in the resolution of acute inflammation. Immunity. 2014;40(3):315–327. PMID:24656045 https://doi.org/10.1016/j.immuni.2014.02.009Chen H, Qin J, Wei P, Zhang J, Li Q, Fu L, et al. Effects of leukotriene B4 and prostaglandin E2 on the differentiation of murine Foxp3+ T regulatory cells and Th17 cells. Prostaglandins Leukot. Essent. Fatty Acids. 2009;80(4):195–200. PMID:19264469 https://doi.org/10.1016/j.plefa.2009.01.006Chen H, Qin J, Wei P, Zhang J, Li Q, Fu L, et al. Effects of leukotriene B4 and prostaglandin E2 on the differentiation of murine Foxp3+ T regulatory cells and Th17 cells. Prostaglandins Leukot. Essent. Fatty Acids. 2009;80(4):195–200. PMID:19264469 https://doi.org/10.1016/j.plefa.2009.01.006D’Alessio FR, Tsushima K, Aggarwal NR, West EE, Willett MH et al. CD4+CD25+Foxp3+ Treg cells resolve experimental lung injury in mice and are present in humans with acute lung injury. J Clin Invest. 2009;119(10):2898–2913. PMID:19770521 https://doi.org/10.1172/JCI36498D’Alessio FR, Tsushima K, Aggarwal NR, West EE, Willett MH, Britos MF, et al. CD4+CD25+Foxp3+ Treg cells resolve experimental lung injury in mice and are present in humans with acute lung injury. J Clin Invest. 2009;119(10):2898–2913. PMID:19770521 https://doi.org/10.1172/JCI36498Arpaia N, Green JA, Moltedo B, Arvey A, Hemmers S, et al. A distinct function of regulatory T cells in tissue protection. Cell. 2015;162(5):1078–1089. PMID:26317471 https://doi.org/10.1016/j.cell.2015.08.021Arpaia N, Green JA, Moltedo B, Arvey A, Hemmers S, Yuan S, et al. A distinct function of regulatory T cells in tissue protection. Cell. 2015;162(5):1078–1089. PMID:26317471 https://doi.org/10.1016/j.cell.2015.08.021Proto JD, Doran AC, Gusarova G, Yurdagul A Jr, Sozen E, Subramanian M, et al. Regulatory T Cells Promote Macrophage Efferocytosis during Inflammation Resolution. Immunity. 2018;49(4):666–677. PMID:30291029 https://doi.org/10.1016/j.immuni.2018.07.015Proto JD, Doran AC, Gusarova G, Yurdagul A Jr, Sozen E, Subramanian M, et al. Regulatory T Cells Promote Macrophage Efferocytosis during Inflammation Resolution. Immunity. 2018;49(4):666–677. PMID:30291029 https://doi.org/10.1016/j.immuni.2018.07.015Ip WKE, Hoshi N, Shouval DS, Snapper S, Medzhitov R. Antiinflammatory effect of IL-10 mediated by metabolic reprogramming of macrophages. Science. 2017;356(6337):513–519. PMID:28473584 https://doi.org/10.1126/science.aal3535Ip WKE, Hoshi N, Shouval DS, Snapper S, Medzhitov R. Antiinflammatory effect of IL-10 mediated by metabolic reprogramming of macrophages. Science. 2017;356(6337):513–519. PMID:28473584 https://doi.org/10.1126/science.aal3535Newson J, Stables M, Karra E, Arce-Vargas F, Quezada S, Motwani M, et al. Resolution of acute inflammation bridges the gap between innate and adaptive immunity. Blood. 2014;124(11):1748–1764. PMID:25006125 https://doi.org/10.1182/blood-2014-03-562710Newson J, Stables M, Karra E, Arce-Vargas F, Quezada S, Motwani M, et al. Resolution of acute inflammation bridges the gap between innate and adaptive immunity. Blood. 2014;124(11):1748–1764. PMID:25006125 https://doi.org/10.1182/blood-2014-03-562710Sutmuller RP, van Duivenvoorde LM, van EA, Schumacher TN, Wildenberg ME, Allison JP, et al. Synergism of cytotoxic T lymphocyteassociated antigen 4 blockade and depletion of CD25(+) regulatory T cells in antitumor therapy reveals alternative pathways for suppression of autoreactive cytotoxic T lymphocyte responses. J Exp Med. 2001;194(6):823–832. PMID:11560997 https://doi.org/10.1084/jem.194.6.823Sutmuller RP, van Duivenvoorde LM, van Elsas A, Schumacher TN, Wildenberg ME, Allison JP, et al. Synergism of cytotoxic T lymphocyteassociated antigen 4 blockade and depletion of CD25(+) regulatory T cells in antitumor therapy reveals alternative pathways for suppression of autoreactive cytotoxic T lymphocyte responses. J Exp Med. 2001;194(6):823–832. PMID:11560997 https://doi.org/10.1084/jem.194.6.823Galdeano CM, Cazorla SI, Lemme-Dumit JM, Vélez E, Perdigón G. Beneficial Effects of Probiotic Consumption on the Immune System. Ann Nutr Metab. 2019;74(2):115–124. PMID:30673668 https://doi.org/10.1159/000496426Galdeano CM, Cazorla SI, Lemme-Dumit JM, Vélez E, Perdigón G. Beneficial Effects of Probiotic Consumption on the Immune System. Ann Nutr Metab. 2019;74(2):115–124. PMID:30673668 https://doi.org/10.1159/000496426Lemme-Dumit JM, Polti MA, Perdigón G, Galdeano CM. Probiotic bacteria cell walls stimulate the activity of the intestinal epithelial cells and macrophage functionality. Benef Microbes. 2018;9(1):153–164. PMID:29124968 https://doi.org/10.3920/BM2016.0220Lemme-Dumit JM, Polti MA, Perdigón G, Galdeano CM. Probiotic bacteria cell walls stimulate the activity of the intestinal epithelial cells and macrophage functionality. Benef Microbes. 2018;9(1):153–164. PMID:29124968 https://doi.org/10.3920/BM2016.0220

The authors declare that there are no conflicts of interest present.